The guideline group was selected to be representative of UK based medical experts and patients representatives. Recommendations are based on a review of the literature using Medline/Pubmed searches under the heading, chronic lymphocytic leukaemia, up to August 2011, and data presented at the American Society of Haematology in 2011. The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemato-oncology Task Force of the British Committee for Standards in Haematology (BCSH). The guideline was then reviewed by a sounding board of approximately 50 UK haematologists, the British Committee for Standards in Haematology (BCSH) and the British Society for Haematology Committee and comments incorporated where appropriate. The ‘GRADE’ system was used to quote levels and grades of evidence, details of which are available in the BCSH guideline pack http://www.bcshguidelines.com/BCSH_PROCESS/42_EVIDENCE_LEVELS_AND_GRADES_OF_RECOMMENDATION.html. The objective of this guideline is to provide healthcare professionals with clear guidance on the management of patients with chronic lymphocytic leukaemia. In all cases individual patient circumstances may dictate an alternative approach.
The age-adjusted incidence rate of CLL in the UK and USA is 4·2 per 100 000 per year. The incidence increases with age, is higher in men than women and higher in Caucasians than in other racial groups. The median age at presentation is 72 years and 11% of patients are diagnosed under the age of 55 years (Howlader et al, 2012).
Epidemiological surveys have shown a sevenfold increase in CLL and a 2·5-fold increase in other lymphoid malignancies, especially lymphoplasmacytoid lymphoma and hairy cell leukaemia, in the relatives of patients with CLL (Goldin et al, 2009). Genome-wide association studies, genotyping single nucleotide polymorphisms in large numbers of patients with CLL and controls provide evidence for a series of loci associated with slightly increased susceptibility to CLL (Di Bernardo et al, 2008; Enjuanes et al, 2008; Crowther-Swanepoel et al, 2010).
- In view of the low absolute risk of CLL developing in a family member of a patient with CLL and the absence of clinical benefit associated with early diagnosis, there is no current indication to screen family members for the presence of a circulating clonal B cell population (unless they are potential allogeneic haemopoietic stem cell transplant donors) or for genetic susceptibility (Grade B1).
The diagnosis of CLL is currently based on the combination of lymphocyte morphology, the presence of >5 × 109/l circulating clonal B cells persisting for >3 months and a characteristic immunophenotype (Bene et al, 2011). A recommended scoring system allocates one point each for the expression of weak surface membrane immunoglobulins, CD5, CD23, and absent or low expression of CD79b and FMC7 (Moreau et al, 1997). Using this system, 92% of CLL cases score 4 or 5, 6% score 3 and 2% score 1 or 2.
The differential diagnosis of a CD5-positive chronic lymphoproliferative disorder with a low score includes CLL, especially cases with atypical lymphocyte morphology and/or trisomy 12 (Cro et al, 2010), mantle-cell lymphoma and marginal zone lymphomas. Additional investigations, including cytogenetic analysis and histology, may be required to obtain a definitive diagnosis (Dronca et al, 2010).
Three disorders, namely CLL, ‘clinical’ CD5+ve monoclonal B cell lymphocytosis (cMBL), i.e., those cases of MBL with a lymphocytosis detectable on a routine full blood count, and small lymphocytic lymphoma (SLL) share a common immunophenotype, lymphocyte morphology and/or histology and similar biological features (Marti et al, 2005; Hallek et al, 2008; Muller-Hermelink et al, 2008; Rawstron & Hillmen, 2010; Gibson et al, 2011)). Distinguishing features are shown in Table 1.
|Clonal B lymphocytes > 5 × 109/l||Y||N||N|
|Lymphadenopathy and/or splenomegaly||Y/N||N||Y|
Clinical and laboratory evaluation
Patients may present with lymphadenopathy, systemic symptoms such as tiredness, night sweats and weight loss or the symptoms of anaemia or infection. However, more than 80% of patients are now diagnosed as an incidental finding on a routine full blood count. Clinical evaluation should elicit a family history of lymphoid malignancy, define the clinical stage (Table 2) and determine whether B symptoms (fever, weight loss, night sweats), profound lethargy and cytopenias are CLL-related, due to marrow infiltration, immune destruction or hypersplenism, or have an alternative cause.
|A||<3 Lymphoid areasa|
|B||≥3 Lymphoid areas|
|C||Haemoglobin < 100 g/l or platelet count < 100 × 109/l|
|RAI Stage||Risk group|
|II||Intermediate||Hepatomegaly or splenomegaly + lymphocytosis|
|III/IV||High||Haemoglobin < 110 g/l or platelet count < 100 × 109/l|
The investigation of asymptomatic stage A patients at diagnosis should include: full blood count, reticulocyte count, direct antiglobulin test (DAT), immunophenotype, routine biochemistry and serum immunoglobulins. Additional tests required pre-treatment, include screening for TP53 deletion and for hepatitis B and C infection in patients who are to receive intensive chemotherapy and/or immunotherapy. Human immunodeficiency virus (HIV) testing should be performed according to UK national guidelines [British HIV Association (BHIVA), 2008].
Marrow examination is not essential for the diagnosis of CLL, but is mandatory to define complete response. It is also indicated in determining the cause of cytopenias pre treatment and prolonged cytopenias post-treatment.
Lymph node biopsy is indicated when there is diagnostic uncertainty or clinical suspicion of lymphomatous transformation (see below).
While computerized tomography (CT) scanning is mandatory in patients entered into clinical trials, the role of imaging in routine practice remains controversial. CT scanning has the potential to identify small volume nodal and/or splenic enlargement in patients who would otherwise be diagnosed as having cMBL or stage A, Rai 0 disease, to identify bulky disease in previously untreated or relapsed patients with no other indication for therapy, to provide a more accurate assessment of treatment response and to detect incidental abnormalities which might influence clinical management. Very few studies have addressed the clinical benefits of this additional information (Hallek et al, 2008; Norin et al, 2010; Eichhorst et al, 2011). There is no evidence to support the routine use of imaging in asymptomatic stage A CLL or cMBL (Muntanola et al, 2007; Scarfo et al, 2012). If there is clinical concern regarding the possibility of significant thoracic, abdominal or pelvic nodal disease, or of disease transformation, then a CT scan is indicated using standard indolent lymphoma protocols. Consensus UK expert opinion supports the routine use of pre- and post-treatment CT scans in patients managed with more intensive therapies. There is no evidence to support on-going routine CT surveillance scanning of asymptomatic patients following treatment for CLL.
- Patients should be screened for a TP53 deletion pre-treatment (Grade A1).
- Patients receiving intensive chemo- or immune-therapy should be screened for hepatitis B and C infection (Grade A1).
- Pre- and post-treatment CT scanning should be considered for patients treated with more intensive therapies. There is no role for routine surveillance CT scans in asymptomatic patients post-treatment (Grade C2).
Diagnosis of lymphomatous transformation
Lymphomas develop in 5–15% of patients with CLL, either pre- or post-therapy. The varying incidence partly reflects the requirement for histological diagnosis and differing policies on the indications for tissue biopsy in CLL (Tsimberidou & Keating, 2005; Rossi et al, 2008, 2009). Histological appearances resemble diffuse large B cell lymphoma (DLBCL) in approximately 80% of cases and Hodgkin lymphoma (HL) in the remainder. Clinical features suggestive of lymphomatous transformation include bulky (>5 cm) lymphadenopathy, rapid nodal enlargement, the appearance of extra nodal disease, the development of B symptoms and marked elevation of lactate dehydrogenase (LDH). As lymphomatous transformation may be localized, biopsy should be directed to the most suspicious clinical site. Positron emission tomography (PET)/CT scanning may help in the choice of the lesion to biopsy (Bruzzi et al, 2006).
- The possibility of lymphomatous transformation should be considered in patients with bulky or progressive asymmetric lymphadenopathy, high LDH, extranodal lesions and/or unexplained B symptoms (Grade A1).
The prognosis of patients with CLL is dependent on a variety of patient, disease and treatment-related factors (Table 3). Disease-related factors include biomarkers able to predict prognosis and those able to predict response to specific treatments.
|Treatment-related||Type of treatment|
|Minimal residual disease status|
The Binet and Rai staging systems predict outcome in patients presenting with widespread and/or bulky lymphadenopathy, hepatosplenomegaly or marrow failure but are insensitive to the clinical heterogeneity within early CLL, i.e. those cases with a low tumour burden who have Binet stage A or Rai stage 0/1 disease (Rai et al, 1975; Binet et al, 1977). Adding simple clinical and laboratory parameters, such as age, gender, lymphocyte count, lymphocyte doubling time (LDT) and serum beta 2 microglobulin (B2M) to clinical stage improves the prediction of overall survival (OS) (Wierda et al, 2007; Shanafelt et al, 2009a) and time to first treatment in early stage CLL (Molica et al, 2010; Bulian et al, 2011).
These parameters and an increasing number of biomarkers (reviewed in Dal-Bo et al, 2009; Furman, 2010; Stamatopoulos et al, 2010) enable patients to be classified as being at low, intermediate or high risk of disease progression. However, the difficulty of extrapolating population data to individual patients is highlighted by recent studies identifying a small subset of stage A patients with TP53 abnormalities who, nevertheless have stable disease (Best et al, 2009; Tam et al, 2009).
Although there is no current evidence that prognostic data should influence the timing of initial therapy in individual patients, we recognize that some patients will still wish to have the clearest possible idea of the likely natural history of their disease. If biomarkers are measured, then a minimum set of investigations should include IGHV gene analysis, serum B2M (interpreted in relation to renal function) CD38 expression and a screen for genomic abnormalities. The results must be interpreted in the clinical context, especially taking account of the patient's age, significant comorbidities and evidence of disease progression since diagnosis (Shanafelt et al, 2010).
- Measurement of prognostic biomarkers is not currently recommended for patients with early CLL in whom there is no clinical indication for treatment (Grade B2).
- Identifying a TP53 abnormality in patients with no clinical indication for therapy is not an indication for treatment (Grade B1).
TP53 loss occurs in 5–10% of patients at the time of initial therapy and in 30% of patients with fludarabine-refractory disease. A further 5% of patients prior to initial therapy and 12% with refractory disease, have a TP53 mutation without loss of the other allele and would not be detected by fluorescence in situ hybridization (FISH) (Stilgenbauer et al, 2009; Oscier et al, 2010; Zenz et al, 2010a; Gonzalez et al, 2011; Pospisilova et al, 2012). Both retrospective and prospective studies of previously untreated patients and those with relapsed CLL show that patients with TP53 loss and/or mutation, have a significantly lower response rate and short progression-free survival (PFS) and OS, when treated with an alkylating agent, purine analogue, bendamustine, mitoxantrone and rituximab alone or in combination (Table 4). In contrast, TP53 status has much less effect on the response of patients treated with agents such as alemtuzumab, which kill CLL cells through a TP53-independent mechanism.
|Study||Patients (n)||Patient characteristics||% with TP53 mutation||% with 17p loss||% with TP53 mutation without 17p loss||Outcome|
|Zainuddin et al (2011)||268||At diagnosis 77% stage A||3·7||3·7||1·1||Both TP53 mutation and del 17p associated with TTFT and OS|
|Rossi et al (2009)||297||At diagnosis 75% stage A||10·0||12·7||3·0||TP53 mutations were an independent predictor of short OS|
|Zenz et al (2010a) (GCLLSG: CLL4 trial)||328||At trial entry F v FC||8·5||4·8||4·5||TP53 mutations were the strongest predictor of short PFS and OS in multivariate analyses|
|Gonzalez et al (2011) (UK LRF: CLL4 trial)||529||At trial entry Chlor v F v FC||7·6||6·3||3·0||TP53 mutations were the strongest predictor of short PFS in multivariate analyses|
|Zenz et al (2010b) (GCLLSG: CLL8 trial)||767||F-refractory||43·8||34·4||N/A|
|PFS 6–12 months||23·5||28·1||N/A|
|PFS 12–24 months||18·1||11·3||N/A|
|PFS > 24 months||4·1||1·5||N/A|
|Zenz et al (2009) (GCLLSG: CLL2H trial)||F-refractory treated with alemtuzumab||37||32·3||12·1||No report of TP53 mutation or 17p loss on outcome|
Unmutated IGHV genes, use of the stereotypic IGHV3-21, deletion of 11q and a raised B2M, independent of clinical stage, also correlated with reduced PFS and OS in a clinical trial of alkylating agent and purine analogue treatment (Oscier et al, 2010). Data from the CLL8 trial comparing FC v FCR indicates that the adverse prognostic significance of del11q may be largely overcome by the addition of rituximab to FC (Hallek et al, 2010). It is currently unclear whether the combination of an anti CD20 antibody with other chemotherapy regimens also improves the outcome of patients with del11q.
- Patients should be screened for the presence of a TP53 abnormality prior to initial and subsequent treatment. Currently, TP53 loss should be assessed by FISH. Patients should also be screened for TP53 mutations when this assay becomes routinely avaliable (Grade B2).
- Measurement of biomarkers other than TP53 loss is not currently recommended outside clinical trials in patients for whom there is a clinical indication for therapy (Grade C2).
Indications for treatment
Patients with active disease, as defined in the International Workshop on Chronic Lymphocytic Leukaemia (IWCLL) guidelines (Hallek et al, 2008), usually benefit from anti leukaemic therapy (Table 5). These criteria apply to both previously untreated and relapsed patients. Neither a high lymphocyte count, in the absence of a rapid LDT or clinical features of hyperviscosity, nor hypogammaglobulinaemia in the absence of serious or recurrent infection is an indication for treatment. The timing of treatment, especially in asymptomatic patients, depends in part upon the rate of disease progression. It is important not to delay treatment to the point at which it may be less effective and/or more difficult to administer (e.g. due to cytopenias) especially in patients with ‘high risk’ CLL.
|Evidence of progressive marrow failure as manifested by the development of, or worsening of, anaemia and/or thrombocytopenia|
|Massive (i.e., at least 6 cm below the left costal margin) or progressive or symptomatic splenomegaly.|
|Massive nodes (i.e., at least 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy.|
|Progressive lymphocytosis with an increase of more than 50% over a 2-month period or lymphocyte doubling time (LDT) of <6 months. In patients with initial blood lymphocyte counts <30 × 109/l, LDT should not be used as a single parameter to define a treatment indication.|
|Autoimmune anaemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy.|
|Constitutional symptoms, defined as any one or more of the following disease-related symptoms or signs|
|Unintentional weight loss of 10% or more within the previous 6 months;|
|Significant fatigue (i.e., Eastern Cooperative Oncology Group Performance Score 2 or worse; inability to work or perform usual activities);|
|Fever higher than 38·0°C for two or more weeks without other evidence of infection; or|
|Night sweats for more than 1 month without evidence of infection.|
Factors influencing the choice and duration of treatment
The clinical heterogeneity of CLL and advanced age of many patients dictate that no single treatment approach is applicable to all patients.
Factors influencing the choice of treatment include an assessment of fitness to tolerate chemotherapy and/or immunotherapy, TP53 status, previous or current immune cytopenias and evidence of lymphomatous transformation (Goede & Hallek, 2011). In previously treated patients, the number and nature of prior treatments, their efficacy and toxicity and the availability of a transplant donor should all be taken into consideration.
Assessing fitness for treatment
Patients requiring treatment should be assessed for their ability to tolerate myelosuppressive and immunosuppressive therapies. Important factors include age, performance status, significant co-morbid conditions, especially a creatinine clearance of <60 ml/min and susceptibility to infection. The use of scoring systems, such as the Cumulative Illness Rating Scale (CIRS) score may be helpful, but none of the currently used scores is CLL-specific and careful assessment of individual patients remains paramount (Miller et al, 1992; Extermann et al, 1998). Although the outcome of patients over the age of 65–70 years entered into clinical trials of FC and FCR was comparable to that of younger patients (Catovsky et al, 2007; Hallek et al, 2010), this data should not be extrapolated to elderly patients with co-morbidities, as these patients have a higher incidence of myelosuppression, often fail to tolerate a full course of treatment and generally have a poorer outcome with therapy (Tam et al, 2008).
Importance of achieving a maximal response
Almost all clinical trials have shown that the better a patient responds to therapy the longer their remission, especially in the absence of detectable minimal residual disease (MRD) (Moreton et al, 2005; Bosch et al, 2008). Recent data from the German CLL8 trial showed an improvement in the depth of remission between cycles 3 and 6, and that achieving an MRD negative remission is an independent marker for improved OS as well as PFS (Bottcher et al, 2012). These data provide a clear rationale for the use of the most effective available initial treatment and for completing six cycles of treatment providing toxicity is acceptable.
Definitions of response, relapse, refractory and high risk disease
IWCLL criteria for complete response (CR), partial response (PR) and progressive disease are shown in Table 6. The IWCLL define relapse as disease progression at least 6 months after achieving a CR or PR. Refractory disease is currently defined as treatment failure or disease progression within 6 months of anti-leukaemic therapy. However, the duration of response that should influence the choice of second line therapy is an area of continuing debate (Zenz et al, 2012). Patients entered into the German CLL8 trial who had a PFS of <12, 12–24 or >24 months had an OS from the time of second line treatment of 13·1, 20·3 and 44·6 months respectively (Stilgenbauer & Zenz, 2010).
|Lymphadenopathy||A||None > 1·5 cm||Decrease ≥ 50%||Increase ≥ 50%|
|Hepatomegaly||A||None||Decrease ≥ 50%||Increase ≥ 50%|
|Splenomegaly||A||None||Decrease ≥ 50%||Increase ≥ 50%|
|Blood Lymphocytes||A||<4·0 × 109/l||Decrease ≥ 50% from baseline||Increase ≥ 50% over baseline|
|Marrow||A||Normocellular, < 30% lymphocytes, no B-lymphoid nodules||50% reduction in marrow infiltrate or B-lymphoid nodules|
|Platelet count||B||>100 × 109/l||>100 × 109/l or increase ≥ 50% over baseline||Decrease of ≥ 50% from baseline secondary to CLL|
|Haemoglobin||B||>110 g/l||>11 g/dl or increase ≥ 50% over baseline||Decrease of >20 g/l from baseline secondary to CLL|
|Neutrophils||B||>1·5 × 109/l||>1500/μl or >50% improvement over baseline|
In a single centre study, 33 of 112 patients who relapsed after initial treatment with FCR were retreated with FCR. Those patients who relapsed after 3 years had an overall response rate (ORR) and CR of 86% and 23%, respectively, compared to 54% and 0% for those relapsing within 3 years (Keating et al, 2009).
Previously untreated or relapsed patients with a TP53 abnormality who require therapy and those who relapse within 2 years of, or are refractory to purine analogue-based therapy regardless of biomarker results, are considered to have ‘high risk’ CLL. These patient groups have a poor outcome when treated conventionally and should be considered for alternative therapies as discussed in section 4.5.4.
Management of patients with no immediate indication for treatment
A diagnosis of stage A CLL is associated with an increased incidence of infections and auto-immune cytopenias. The quality of life of patients and family/partners may also be affected by a variety of factors including use of the term ‘leukaemia’, uncertainty about the long-term outlook, concerns about transmission of the disease to offspring and practical issues such as difficulties in obtaining insurance. These issues should be explored and addressed at presentation and regularly during the course of the disease (Shanafelt et al, 2007, 2009b; Evans et al, 2012). The issue of patient communication from both the haematologist's and patient's perspective is discussed on the UK CLL Forum website (www.ukcllforum.org).
Patients with early CLL should be reviewed at least twice within the first year from diagnosis to assess the rate of disease progression. For those with stable disease, particularly if they have ‘good risk’ clinical and/or laboratory features, monitoring can be extended to an annual check. This may be performed in primary care (providing there are clear local guidelines for specialist referral), or in hospital clinics (medical, nurse practitioner or via teleclinics) depending on local arrangements.
A meta-analysis of 2048 patients in six trials of immediate treatment with chlorambucil plus or minus prednisolone versus deferred treatment showed no significant difference in 10-year-survival (CLL Trialists' Collaborative Group, 1999). The benefits of early versus delayed treatment using FCR, FR or lenalidomide in asymptomatic early stage patients with poor risk prognostic factors are currently being evaluated in randomized trials.
- Treatment of early stage disease is not currently indicated (Grade A1).
- Treatment options are provided based on fitness to tolerate FCR chemo-immunotherapy and whether patients are previously untreated or have relapsed or high-risk disease.
- The recommendations given below are largely based on the results of clinical trials, especially phase III studies. However, it is recognized that many elderly patients are excluded from trials due to co-morbidities.
- The inclusion of patients who may be either minimally or heavily pretreated and who may have either refractory or responsive disease, makes the results of many second line studies difficult to interpret.
- Clinical trials employing cladribine or pentostatin rather than fludarabine have not shown convincing evidence of improved efficacy over fludarabine and their use outside clinical trials is not recommended (Robak et al, 2006, 2010; Kay et al, 2007; Reynolds et al, 2008).
- BCSH guidelines recommend the use of irradiated blood products in the following situations: indefinitely in patients treated with a purine analogue, following bendamustine until more evidence emerges about the risk of transfusion-associated graft-versus-host disease, following alemtuzumab and for 3 months post-conditioning with chemotherapy or immunotherapy (6 months afer total body irradiation) for patients undergoing autologous transplantation (Treleaven et al, 2011)
- Therapeutic agents with marketing authorisaization for use in the UK, their licensed indications, current National Institute for Health and Clinical Excellence (NICE) and Scottish Medicines Consortium (SMC) guidance for the management of CLL and details of current National Cancer Research Institute (NCRI) CLL trials are available on the UK CLL Forum website (www.ukcllforum.org).
- A retrospective survey of the outcome of patients with CLL managed by either a haemato-oncologist specializing in CLL or in another haematological malignancy showed an improved OS for patients managed by CLL experts after adjusting for age, gender, stage and lymphocyte count at diagnosis (Shanafelt et al, 2012). This supports the UK model of discussing the management of patients with CLL, including those with Stage A disease, at an multidisciplinary team meeting attended by a haematologist experienced in the management of CLL.
Initial treatment of fit patients with no TP53 abnormality
Table 7 summarizes the results of recent phase III trials that showed an improved outcome for patients treated with FC compared to F or chlorambucil (Eichhorst et al, 2006; Catovsky et al, 2007; Flinn et al, 2007) and with FCR compared to FC (Hallek et al, 2010).
|Study||Regimen||Patients (n)||Median age (years)||CR (%)||OR (%)||Median PFS (months)||Median OS (%)||Grade 3–4 neutropenia (%)|
|Eichhorst et al (2006)||FC||180||58||24||94||48||81 (3 years)||26|
|F||182||59||7||83||20||80 (3 years)||56|
|Flinn et al (2007)||FC||141||61||23||74||32||NA||69|
|Catovsky et al (2007)||FC||196||65||38||94||43||54 (5 years)||56|
|F||194||64||15||80||23||52 (5 years)||41|
|Hallek et al (2010)||FC||409||61||22||80||33||NA||21|
Phase II studies have demonstrated the efficacy of FR (Woyach et al, 2011), BR (Fischer et al, 2009) and FCMR (fludarabine + cyclophosphamide + mitoxantrone + rituximab) (Bosch et al, 2009) (Table 8), and Phase III studies comparing these regimens with FCR are in progress.
|Study||Regimen||Patients (n)||Median age (years)||CR (%)||OR (%)||Median PFS (months)||Median OS (months)||Grade 3–4 neutropenia (%)|
|Byrd et al (2003) updated by Woyach et al (2011)||FR||104||63||42||85|
|Bosch et al (2008)||FCM||69||NA||64||90||37||NA||10|
|Bosch et al (2009)||FCMR||72||60||82||93||NA||NA||13|
|Tam et al (2008)||FCR||300||57||72||95||80||77 (6 years)|
|Lamanna et al (2009)||FCR (sequential)||36||59||61||89||43||71 (5 years)||NA|
|Wierda et al (2011)||FC O (low dose)||31||56||50||77||NA||NA||48|
|FC O (high dose)||30||32||73||NA||NA|
|Fischer et al (2009)||BR||117||64||33||91||NA||NA||15|
- FCR is recommended as initial therapy for previously untreated fit patients outside clinical trials (Grade A1).
- Patients who progress after one cycle of FCR or who have stable disease after two cycles have high-risk disease and should be managed accordingly (section 4.5.5).
Initial treatment of unfit patients with no TP53 abnormality
Chlorambucil remains widely used in the UK for patients considered unfit for intensive therapy. Although there is no international consensus as to the optimal dose or duration of chlorambucil therapy, the highest response rate and longest PFS have been reported in the UK Leukaemia Research Fund (LRF) CLL4 trial in which chlorambucil was administered at a dose of 10 mg/m2/d for 7 d every 4 weeks initially for 6 months extending to 12 months, in patients still responding after 6 months treatment (Catovsky et al, 2011).
The results of phase 3 studies comparing single agent chlorambucil with other regimens are given in Table 9 and show no benefit for single agent fludarabine over chlorambucil.
|Study||Regimen||Patients (n)||Median age (years)||CR (%)||OR (%)||Median PFS (months)||Grade 3–4 neutropenia (%)|
|Rai et al (2000)||F||179||64||20||63||20||27|
|Catovsky et al (2007)||F||194||64||15||80||23||41|
|Eichhorst et al (2009)||F||93||71||7||72||19||12|
|Hillmen et al (2007)||A||149||59||24||83||15||41|
|Knauf et al (2009)||B||162||63||31||68||22||23|
A recent phase III study randomized patients to chlorambucil or bendamustine (Knauf et al, 2009) and showed a higher response rate and longer PFS for the bendamustine arm. The ORR and PFS in the chlorambucil arm was lower than in the UK LRF CLL4 trial but comparisons between the two studies are hampered by the use of different chlorambucil dose regimens and differing inclusion criteria.
Preliminary data from phase II studies are shown in Table 10. A higher ORR (80% vs. 66%) was achieved with the combination of chlorambucil and rituximab compared to a historical control arm derived from patients receiving single agent chlorambucil in the UK CLL4 trial (Hillmen et al, 2010). A similarly high ORR of 91% was obtained in 117 patients, of whom 26% were over the age of 70 years, treated with bendamustine and rituximab (BR) (Fischer et al, 2009). Phase III trials of chlorambucil or bendamustine in combination with an anti-CD20 antibody are in progress.
|Study||Regimen||Patients (n)||Median age (years)||CR (%)||OR (%)||Median PFS (months)||Grade 3–4 neutropenia (%)|
|Hillmen et al (2010)||C+R||100||70||9||82||NA||39|
|Castro et al (2009)||HDMPR||28||65||32||96||30||3|
|Forconi et al (2008)||FC||14||71||83·5||100||48||28|
|Badoux et al (2011)||Lenalidomide||60||10||65||60||34|
In view of the efficacy of FC and FCR in CLL, small non-randomized phase II studies have evaluated dose-reduced regimens in patients considered unfit for full dose treatment. (Forconi et al, 2008; Smolej et al, 2010) Although high response rates with acceptable toxicity are achievable, larger randomized studies with prolonged follow up are necessary to evaluate this treatment approach (Mulligan et al, 2010).
Recommendations (Grade B1)
- Options for patients unfit for FCR include chlorambucil or bendamustine.
- Entry of patients into trials of chlorambucil or bendamustine in combination with anti CD20 antibodies is strongly encouraged.
- Further studies are required to determine the efficacy of dose-reduced FC or FCR.
Management of relapsed CLL with no TP53 abnormality
Patients who relapse and have not acquired a TP53 abnormality can be expected to respond to a further course of their initial therapy, although the PFS is usually shorter than after initial therapy and repeated courses often lead to drug resistance. However, re-treatment with the previous therapy is not recommended in patients whose initial treatment was sub-optimal or if a new treatment, shown to be superior to the initial therapy, becomes available.
The results of studies that include patients with relapsed disease are shown in Table 11. Specific recommendations for patients relapsing after FC or FCR and for patients relapsing after or refractory to chlorambucil, are provided below.
|Study||Regimen||Patients (n)||Refractory Patients (%)||Median age (years)||Median number of prior treatments||CR (%)||OR (%)||Median PFS (months)||Median OS(months)||Grade 3–4 neutropenia (%)|
|Robak et al (2010)||FCR||276||0||63||1||24||70||30·6||89|
|Badoux et al (2011)||FCR||230||0||60||2||36||79||28||52|
|Fischer et al (2011)||BR||78||28 (F)||67||2||9||59||15||23·1|
|Iannitto et al (2011)||B||22||57||66||3||32·5||70||16||17|
|Hillmen et al (2011)||FCMR||26||42||65||NA||NA|
|Castro et al (2008)||R + HDMP||14||100 (F)||59||2||36||93||15||NA|
|Dungarwalla et al (2008)||R + HDMP||14||100 (F)||62||2||14||93||7||20|
|Elter et al (2011)||F||167||40||60||1||4||75||16·5||32·9||68|
Relapse at least 2 years after fludarabine combination chemotherapy or chemo-immunotherapy
There are no phase III studies of patients relapsing after FC or FCR. A non-randomized phase II study of FCR in 284 patients with relapsed CLL showed a higher CR rate and longer PFS and OS than seen in a historical cohort treated with FC. Seventy-eight out of two-hundred and eighty-four patients received prior therapy with regimens that included fludarabine and an alkylating agent. Thirteen per cent and 9% were refractory to fludarabine and chlorambucil respectively. The ORR was 73% with 42% CR + nodular PR (nPR) and the PFS was 19 months. The CR + nPR rate for fludarabine-responsive cases was 46% compared to 8% for fludarabine-refractory cases (O'Brien et al, 2001; Badoux et al, 2011).
A non-randomized phase II study of BR has shown response rates of 60% and 45% for relapsed or fludarabine-refractory patients, respectively, with an event-free survival (EFS) of 14·7 months. Only 2/14 patients with a 17p deletion responded (Fischer et al, 2008; Iannitto et al, 2011).
Recommendation (Grade B2)
- Patients relapsing at least 2 years after FC, FCR or similar regimens who have not acquired a TP53 abnormality, remain fit enough for fludarabine-based treatment and in whom there is a clinical indication for treatment, should receive FCR.
- Further studies are required to evaluate the role of bendamustine in combination with an anti-CD20 antibody in fit patients with relapsed disease.
Relapse after or refractory to chlorambucil
Most patients who relapse after chlorambucil will respond to retreatment with chlorambucil.
The phase II trials of BR discussed in the previous section included elderly patients and the acceptable toxicity indicated that this regimen may be suitable for relapsed or refractory patients unfit for FCR.
The REACH study randomized patients relapsing predominantly after single agent alkylating or purine analogue therapy to FC v FCR and showed an improved ORR, CR and PFS in the FCR arm (Robak et al, 2010).
Recommendation (Grade B2)
- Patients relapsing after chlorambucil can be retreated with chlorambucil.
- Entry into trials that include bendamustine or chlorambucil and an anti-CD20 antibody is strongly recommended.
- In the absence of a suitable trial, BR should be considered for patients refractory to chlorambucil.
- The minority of patients relapsing after chlorambucil who are fit enough to receive fludarabine-based therapy should be considered for FCR.
- Other options for patients who are refractory to chlorambucil and unable to tolerate myelosuppressive therapy include high dose steroids, alone or in combination with rituximab, and alemtuzumab.
Management of High-risk CLL
There have been no randomized studies specifically for patients with high risk CLL (TP53 defect and/or failing fludarabine combination therapy within 2 years). The results of phase II and III studies using either FC, FCR, or alemtuzumab with or without high dose steroids and included previously untreated patients with a TP53 abnormality are shown in Table 12. FCR and alemtuzumab are associated with similar response rates and PFS. However, combination therapy with alemtuzumab and pulsed high-dose glucocorticoids achieves response rates and PFS superior to those achieved with FCR or alemtuzumab alone. Consequently, alemtuzumab plus pulsed methylprednisolone or dexamethasone should be regarded as the induction regimen of choice. This regimen is associated with a significant risk of infection and meticulous attention should be paid to antimicrobial prophylaxis and supportive care. Routine antimicrobial prophylaxis with oral co-trimoxazole, aciclovir and itraconazole and monitoring for cytomegalovirus (CMV) reactivation is recommended.
|Study||Regimen||Patients (n)||CR (%)||OR (%)||Median PFS (months)||OS (%)|
|Hallek et al (2010)||FC||29||4||45||0 (2 years)||41 at 2 years|
|Hillmen et al (2007)||A||11||64||11||NA|
|Pettitt et al (2012)||A + HDMP||17||65||100||18·3||38·9 (median)|
|Stilgenbauer et al (2011)||A + Dex||30||20||97||16·9||NA|
As the duration of remission following alemtuzumab-containing regimens is relatively short, consolidation with allogeneic transplantation (see below) is recommended in suitable patients.
Treatment of relapsed/refractory diease
The results of studies of fludarabine-refractory CLL are shown in Table 13. The outcome of fludarabine-refractory patients treated with chemotherapy is poor with a median OS of approximately 8 months. Alemtuzumab alone results in an ORR of about 30–35%. Combining alemtuzumab with high-dose steroids results in an improved ORR but the PFS and OS are nevertheless unsatisfactory.
|Study||Regimen||Patients (n)||Median number of prior treatments||CR (%)||OR (%)||Median PFS (months)||Median OS(months)||TP53 abnormality (%)||Fludarabine Refractory (%)|
|Keating et al (2002)||A||93||3||2||33||4·7||16||N/A||100|
|Lozanski et al (2004)||A||36||3||6||31||NA||NA||42||81|
|Stilgenbauer et al (2009)||A||103||3||4||34||7·7||19·1||30||100|
|Pettitt et al (2012)||A + HDMP||22||NA||14||76||6·5||19||100||NA|
|Elter et al (2005)||A + F||36||2||31||83||13||NA||25|
|Wierda et al (2010)||O||59 (FA ref)||5||0||51||5·5||14·2||29|
|78 (BF ref)||4||2||44||5·5||17·4||18|
|Badoux et al (2011)||CFAR||80||3||29||65||10·6||16·7||30 (46 patients tested)||39|
Regimens that include fludarabine and alemtuzumab have activity in patients refractory to either agent alone but responses are not durable and the risk of infectious complications is high (Elter et al, 2005; Badoux et al, 2011).
As with the initial treatment of high-risk disease, the duration of remission following alemtuzumab-containing regimens is short and consolidation therapy, such as allogeneic transplantation (see below), is recommended in suitable patients. For patients for whom allogeneic transplantation is not an option, re-treatment with alemtuzumab should be considered in those patients who relapse more than 12 months after initial treatment (Fiegl et al, 2011).
Treatment options for patients who fail or relapse early after alemtuzumab-based therapy are limited. Active agents include ofatumumab, lenalidomide (Ferrajoli et al, 2008) and high-dose steroids with or without rituximab (Pileckyte et al, 2011). Steroids given at conventional dose can provide useful short-term disease control and improve CLL-related symptoms. The choice of therapy depends on patient fitness, previous treatment and drug availability. In the registration study (Wierda et al, 2010), ofatumumab achieved an ORR of 58% in patients refractory to both fludarabine and alemtuzumab (double refractory) and 47% in patients with bulky, fludarabine-refractory CLL for whom alemtuzumab was considered inappropriate. The median PFS was approximately 6 months for both groups (Wierda et al, 2010). The effectiveness of ofatumumab was not influenced by bulky lymphadenopathy, prior rituximab exposure or refractoriness to FCR. The ORR was lower (14%) among patients with a 17p deletion in the bulky fludarabine-refractory group, but 41% in double refractory 17p deleted disease.
Role of radiotherapy
Radiotherapy should be considered for patients for whom chemo-immunotherapy has been ineffective or is contra-indicated and can provide effective palliation in cases with symptomatic bulky lymphadenopathy. Low doses of external beam radiotherapy (2 × 2 Gy) can be highly effective in this situation and a higher dose (30 Gy in 2–3 Gy fractions) may be required in patients with transformed aggressive disease or those known to have a TP53 abnormality (Lowry et al, 2011).
Recommendations (Grade B1/2)
- The management of high-risk CLL is controversial and poses considerable therapeutic challenges. Accordingly, early input from a centre with a specialist interest in CLL is strongly recommended.
- Treatment for high-risk CLL should ideally be delivered as part of a clinical trial. Outside of trials, alemtuzumab in combination with pulsed high dose glucocorticoid is the treatment of choice. Meticulous attention should be paid to antimicrobial prophylaxis and supportive care.
- The use of alemtuzumab in combination with drugs other than steroids should be confined to clinical trials
- Subcutaneous alemtuzumab injection is associated with comparable efficacy and less toxicity in CLL and this has become the preferred route of administration
- Ofatumumab is the treatment of choice for patients with high-risk CLL who fail alemtuzumab. Other options include high-dose or conventional-dose glucocorticoids, lenalidomide or radiotherapy.
The role of allogeneic transplantation
Allogeneic stem-cell transplantation provides the best opportunity of achieving long-term disease-free survival for patients with high-risk CLL, including those with TP53 abnormalities. An European Group for Blood and Marrow Transplantation (EBMT) retrospective study of 44 transplants performed between 1995 and 2006 for 17p deleted CLL showed that about one-third of patients achieved long-term remission (Schetelig et al, 2008). In the German CLL Study Group CLL3X trial, the 4-year EFS was 42% and was similar for all genetic subtypes (Dreger et al, 2010), indicating that 17p deletion loses its adverse prognostic significance in this therapeutic context.
A comparison of registry data suggests that reduced intensity conditioning (RIC) transplants may be superior to myeloablative transplants – the reduction in disease control using a reduced intensity approach is more than compensated for by the reduction in treatment-related mortality. Recent data from the EBMT suggest that the outcomes following transplants from fully matched unrelated donors are identical to those following transplants from sibling donors and will increase the donor pool (Michallet et al, 2010). Analysis of prospective trials of allografting in CLL suggests that not being in remission has greater adverse prognostic significance than the number of lines of prior therapy (Delgado et al, 2009). Data from the Seattle group also clearly identify the poorer outlook for both overall survival, EFS and non-relapse mortality in patients with co-morbidities (Sorror et al, 2008).
The results of recent allogeneic transplant studies are given in Table 14 and current UK-CLL Forum and British Society for Bone Marrow Transplantation recommendations for allogeneic transplantation in CLL, which incorporate the EBMT consensus indications (Dreger et al, 2007), are shown in Table 15.
|Study||Patients (n)||Median age, years (range)||Transplant||Conditioning Regimen||Donor- related (%)||Extensive cGVHD (%)||PFS,% (median follow-up)||OS,% (median follow-up)|
|Pavletic et al (2005)||38||45 (26–59)||MA||0||30 (5 years)||33 (5 years)|
|Gribben et al (2005)||25||47 (29–55)||MA||100||50||24 (6 years)||55 (6 years)|
|Toze et al (2005)||30||48 (32–59)||MA||66||39 (5 years)||39 (5 years)|
|Schetelig et al (2003)||30||50 (12–63)||RIC||F.B.ATG||50||21||67(2 years)||73 (2 years)|
|Brown et al (2006)||43||53 (35–67)||RIC||F.B.||33||38||34 (2 years)||54 (2 years)|
|Khouri et al (2007)||39||57 (34–70)||RIC||FCR||90||58||44 (4 years)||48 (4 years)|
|Delgado et al (2008)a||41||52 (37–64)||RIC||F.M.A.||78||10||39 (3 years)||65 (3 years)|
|Delgado et al (2008)b||21||54 (34–64)||RIC||F.M||86||48||47 (3 years)||57 (3 years)|
|Sorror et al (2008)||82||56 (42–64)||RIC||F.LD TBI||63||51||39 (5 years)||50 (5 years)|
|Schetelig et al (2008) (all patents had TP53 loss)||44||54 (35–64)||RIC (89%)||Various||54||53||37 (3 years)||44 (3 years)|
|Dreger et al (2010)||90||RIC||FC +/− ATG||42 (4 years)||65 (4 years)|
|Allogenic transplantation is a reasonable treatment option for previously treated patients with poor risk features as defined below|
|European Group for Blood and Marrow Transplant (EBMT) 2006a||UK CLL Forum/British Society for Bone Marrow Transplants (BSBMT) Recommendationsb|
|Non response or early relapse (within 12 months) after purine analogue containing therapy||Relapse within 6 months of purine analogue therapy|
|Relapse within 24 months after purine analogue combination therapy or treatment of similar efficacy, such as autologous transplantation||Relapse within 24 months of intensive therapy including purine analogue/alkylator combinations, chemo-immunotherapy or autologous transplantation|
|Patients with TP53 loss/mutation requiring treatment||Patients with TP53 loss/mutation ideally after maximal response to TP53 independent therapy|
|Patients not fulfilling the above criteria who are in second or subsequent relapse with at least one other commonly recognized adverse feature as follows: bone marrow failure according to Binet criteria, unmutated IGHV genes, high expression of ZAP70 or CD38. deletion of 11q|
In view of the fact that CLL-type MBL is detectable in 3–5% of healthy adults and in 13–18% of siblings of patients with CLL (Rawstron et al, 2002; Marti et al, 2003; Del Giudice et al, 2009), the question arises as to the benefit of screening potential donors, especially family donors, pre-transplant. Information on the outcome of CLL patients whose donor had MBL is very limited and the risk of acquiring progressive CLL from the donor should be balanced against the prognosis of the potential transplant recipient, particularly if no alternative donor or other type of treatment is available (Hardy et al, 2007; Flandrin-Gresta et al, 2010; Herishanu et al, 2010). There is currently no national or international consensus on the need to screen potential donors for MBL. It would seem sensible to exclude donors with either early CLL or cMBL in whom the majority of B lymphocytes are clonal (Rawstron & Hillmen, 2010).
- Allogeneic stem-cell transplantation should be considered as consolidation therapy for all fit patients with high-risk CLL and should ideally be performed in the setting of a secure remission. Suitable patients should be discussed with a transplant centre at the earliest opportunity (Grade B1).
- There is no consensus on the value of screening potential allograft donors for MBL. It would seem sensible to exclude donors with early CLL or cMBL (Grade C2).
The observation that an MRD-negative remission is associated with prolonged PFS, both in previously untreated (Bosch et al, 2008; Tam et al, 2008) and relapsed cases (Moreton et al, 2005), has lead to studies of additional treatment in patients with residual disease post-therapy.
The use of alemtuzumab following initial therapy with fludarabine-based regimens has led to an improved CR rate, MRD eradication and prolonged PFS, but the potential for infective complications necessitates careful attention to the timing of consolidation therapy and to antimicrobial prophylaxis and treatment (Schweighofer et al, 2009; Lin et al, 2010; Varghese et al, 2010; Wierda et al, 2011).
Preliminary data suggest that consolidation therapy with rituximab may prolong PFS (Hainsworth et al, 2003; Del Poeta et al, 2008; Bosch et al, 2010). The role of anti-CD20 antibody therapy and lenolidamide as maintenance/consolidation therapy are currently being evaluated in clinical trials.
- Currently, consolidation and maintenance immunotherapy therapy should only be offered in clinical trials because the clinical benefit versus the risk of morbidity is still uncertain (Grade B2).
Recent phase III studies have evaluated the role of autologous stem cell transplantation in patients who achieve a good response to initial therapy. All showed prolongation of PFS or EFS compared to the observation arm with no improvement in OS (Michallet et al, 2011; Sutton et al, 2011; Brion et al, 2012). The majority of patients had not been exposed to rituximab and it is possible that gains of a similar magnitude might have been achieved with best modern induction therapy.
- In the absence of an OS gain or evidence of improved quality of life, autografting is not recommended as part of standard care in CLL (Grade A1).
Management of lymphomatous transformation
The outcome of CLL patients with lymphomatous transformation is significantly poorer than that of patients presenting with de novo lymphomas with a similar histology. Adverse risk factors include poor performance status, >2 prior therapies, >5 cm lymphadenopathy, clonal identity to the underlying CLL clone and loss or mutation of the TP53 gene (Tsimberidou et al, 2006a; Rossi et al, 2011). There have been no randomized trials on the treatment of aggressive lymphomas that develop in CLL. The ORR for 130 patients treated at the MD Anderson Cancer Centre was 34% for those receiving intensive chemotherapy and 47% for those receiving chemotherapy and rituximab. The median survival was 8 months. Of the patients who achieved a remission, those who underwent allogeneic stem cell transplantation had a longer survival than those receiving no additional therapy or those who underwent allogeneic or autologous transplantation for relapsed or refractory disease (Tsimberidou et al, 2006b). In a separate analysis of 18 patients who developed HL the ORR to ‘Hodgkin like’ chemotherapy was 44% (Tsimberidou et al, 2006a). The median OS was 0·8 years. More recently an ORR of 50% was achieved in 20 patients with lymphomatous transformation treated with a combination of Oxaliplatin, fludarabine, cytarabine and rituximab. The median response duration was 10 months (Tsimberidou et al, 2008).
Options are limited for patients unable to tolerate intensive therapy but palliation might be achieved using a high dose steroid regimen.
- The diagnosis of lymphomatous transformation requires histological confirmation.
- Depending on the histological sub type of lymphomatous transformation, patients who are suitable for intensive therapy should receive regimens currently employed for either primary DLBCL or HL (preferably in the context of a clinical trial). Younger patients who achieve a good response are candidates for allogeneic stem cell transplantation (Grade B2).
Treatment of small lymphocytic lymphoma
Data on the optimal treatment of SLL is limited and patients are often included in studies that include other low grade B cell lymphomas rather than CLL. However, the biological similarities between SLL and CLL are so close that a similar response to treatment could be expected. This is supported by a single centre retrospective study of CLL and SLL that also showed a better outcome for both disorders when treated with regimens that included a nucleoside analogue and rituximab (Tsimberidou et al, 2007).
Indications for, and choices of, treatment are the same as for CLL. The rare patient in whom SLL is diagnosed following biopsy of an enlarged lymph node in the absence of detectable disease at any other site, may be offered local radiotherapy with curative intent.
- SLL should be managed in the same manner as CLL (Grade B2).
Autoimmune complications in CLL
Autoimmune complications are common in CLL, occurring in 10–20% of patients (Hodgson et al, 2011). These almost exclusively target blood cells, most commonly red blood cells. The diagnosis of autoimmune haemolytic anaemia (AIHA) is based on the presence of an isolated fall in haemoglobin accompanied by a positive DAT, a rise in reticulocyte count, bilirubin and LDH, and a fall in serum haptoglobins. Immune thrombocytopenic purpura (ITP) (Visco et al, 2008) is less common (2–5%) and may occur in conjunction with AIHA (Evans syndrome). There is no precise diagnostic test but a fall in the platelet count with no other cause for thrombocytopenia is suggestive. Pure red cell aplasia is rare, but under-recognized, presenting with a fall in haemoglobin an associated reticulocytopenia and a negative DAT. It is important to rule out viral infections [Epstein Barr virus (EBV), CMV and Parvovirus B19] in this disorder. For all auto-immune cytopenias full evaluation usually requires a bone marrow aspirate and trephine biopsy.
Risk factors for developing AIHA include; a positive DAT, advanced stage disease (Stage C), high white blood cell count, older age, male gender and poor prognostic markers (high B2M, unmutated IGHV genes, ZAP70+, CD38+) (Dearden et al, 2008; Moreno et al, 2010; Zanotti et al, 2010) and initiating treatment. The reported incidence of AIHA following specific regimens varies among studies but is lower for FC and FCR than for single agent chlorambucil and fludarabine. (Borthakur et al, 2007; Dearden et al, 2008; Hallek et al, 2010). Data on the incidence of AIHA following bendamustine or BR is more limited but the risk appears to be low (Knauf et al, 2009; Fischer et al, 2011). Chemo-immunotherapy combinations are recommended for patients whose CLL requires treatment and who have a positive DAT or have had a previous immune cytopenia either unrelated to treatment or following alkylating agent/purine analogue therapy. There is little data to inform the subsequent treatment of patients whose immune cytopenia ocurred during chemo-immunotherapy. Options include a switch from FCR to BR and the use of prophylactic immunosuppressive therapy (see below).
There are no controlled trials or systematic studies to inform the treatment of auto-immune cytopenias. A suggested algorithm is shown in Fig 1. The majority of patients respond to steroids but it can be difficult to withdraw treatment and immunosuppressive, steroid-sparing therapy, such as cyclosporine or azathioprine (Cortes et al, 2001), may be a helpful addition to allow this. Intravenous immunoglobulin (0·4 mg/kg/d for 5 d) can be used to induce rapid temporary elevation of counts, particularly in ITP. Splenectomy may be life-saving in patients with very vigorous uncontrolled haemolysis or thrombocytopenia (Hill et al, 2004). Case reports indicate that thrombopoietin receptor agonists may be effective in patients with ITP (Koehrer et al, 2010; Sinisalo et al, 2011).
Low dose cyclophosphamide, rituximab (Ghazal, 2002; D'Arena et al, 2006) and alemtuzumab (Karlsson et al, 2007) have all been used successfully to treat refractory auto-immune cytopenias. Chemo-immunotherapy combinations may also be effective (Kaufman et al, 2009; Bowen et al, 2010). The presence of an auto-immune cytopenia is not in itself an indication to treat the CLL although it may arise in the context of disease progression and may not resolve without CLL-therapy. However, stage C disease due to bone marrow failure has a much worse prognosis than that due to AIHA and/or ITP and successful treatment of immune cytopenias often up-grades the CLL patient to Stage A or B (Zent et al, 2008; Moreno et al, 2010).
Recommendations (Grade B1)
- A bone marrow aspirate is usually required to confirm the diagnosis of auto-immune cytopenia.
- AIHA or ITP should be treated before deciding whether therapy for CLL is needed.
- First line therapy is prednisolone.
- Second line therapies for patients intolerant of or refractory to steroids, include cyclosporine, intravenous immunoglobulin (ITP), thrombopoietin mimetic agents (ITP), low-dose cyclophosphamide, rituximab, alemtuzumab and splenectomy.
- CLL treatment may be initiated to control recurrent or refractory AIHA/ITP. Rituximab –containing regimens are recommended in patients who do not have a TP53 abnormality.
- If AIHA/ITP develops during CLL treatment the same regimen should only be used again in that patient with extreme caution and if no effective alternative is available.
- Autoimmune neutropenia usually responds to granulocyte colony-stimulating factor (GCSF).
Infective complications account for up to 50% of all CLL-related deaths. Risk factors for infection include advanced age, advanced stage, co-morbidities, a history of previous infections, hypogammaglogulinaemia, the number and nature of prior therapies and treatment responsiveness (Hensel et al, 2003).
Anti microbial prophylaxis
Detailed guidance on antimicrobial prophylaxis is beyond the scope of this guideline. Recent reviews on the prevention of infection in CLL (Morrison, 2010), and National Comprehensive Cancer Network guidelines on the prevention and treatment of cancer-related infections (NCCN.org) are recommended.
Important practice points are summarized below:
- Antimicrobial prophylaxis should be considered for patients with hypogammaglobulinaemia who develop recurrent bacterial infections. (Egerer et al, 2001; Hensel et al, 2003; Ravandi & O'Brien, 2006). This may be especially helpful in patients with bronchiectasis, in whom nebulized or low dose oral antibiotics such as azithromycin can reduce the incidence of recurrent infection.
- Anti-Pneumocystis jirovecii prophylaxis is recommended in patients requiring intensive and/or immunosuppressive treatment.
- Anti-herpes simplex virus and herpes zoster virus prophylaxis is recommended in patients requiring intensive and/or immunosuppressive treatment who are seropositive, have a low CD4 count or a history of previous herpes infections.
- The duration of anti-pneumocystis and herpes prophylaxis is controversial. Recommendations range from a minimum of 2 months post-therapy to awaiting a rise in CD4 count to 0·2 × 109/l.
- No prophylaxis is required in patients treated with alkylating agents or bendamustine. The use of prophylaxis is also controversial in fit patients receiving FC or FCR as first line therapy. Data from GCLLSG trials suggests that infection rates are low (Eichhorst et al, 2007).
- GCSF should be administered according to American Society of Clinical Oncology guidelines (Smith et al, 2008).
- Patients receiving alemtuzumab should be monitored for CMV reactivation (O'Brien et al, 2006; Elter et al, 2009; Osterborg et al, 2009).
- Chemotherapy, immunotherapy with anti CD20 antibodies or alemtuzumab and transplantation may result in reactivation of hepatitis B and/or C virus infection. All patients with CLL receiving immunosuppressive therapy should be screened for evidence of previous hepatitis B or C infection. Patients positive for hepatitis B surface antigen (HBSAg) or hepatitis B core antigen (HBCAg) may require antiviral treatment and should be managed jointly with a specialist in viral hepatitis (Artz et al, 2010).
- EBV reactivation should be considered in febrile CLL patients, especially those with high-risk disease (Rath et al, 2008).
- Progressive multifocal leucoencephalopathy (PML) has been reported as a rare complication in patients with chronic B cell lymphoproliferative disorders who have been treated with rituximab.This diagnosis should be considered in CLL patients who develop progressive confusion, weakness, poor motor coordination, speech or visual changes (Carson et al, 2009).
Recomendations (Grade A1)
- All patients should be assessed for risk factors for infection and for current active infection prior to treatment.
- All patients receiving immunosuppressive therapy should be screened for hepatitis B and C infection pre-treatment.
Immunoglobulin replacement therapy
Hypogammaglobulinaemia occurs in 20–70% of unselected patients with CLL. The incidence increases in patients with advanced disease stage, in those with a long disease duration and following immunosuppressive therapy (Hamblin & Hamblin, 2008; Morrison, 2010).
A systematic review and meta analysis of small randomized studies (Raanani et al, 2009) conducted before the introduction of modern immunosuppressive therapy concluded that intravenous immunoglobulin replacement therapy in patients with a history of previous infection and/or low serum IgG levels, resulted in a significant reduction in both major infections and all clinically documented infections compared to a placebo group. There was no significant effect on overall mortality.
In the absence of recent randomized studies, recommendations for the use of immunoglobulin replacement in CLL are largely based on clinical experience and data from its use in primary immunodeficiencies (Egerer et al, 2001).
Recurrent or severe infection with encapsulated bacteria despite prophylactic oral antibiotic therapy in patients with a serum IgG < 5 g/l (excluding a paraprotein).
Department of Health guidelines on immunoglobulin use recommend that if a patient received unconjugated pneumococcal or other polysaccharide vaccine challenge many years ago and specific antibody levels are low, it would be reasonable to re-vaccinate before prescribing immunoglobulin replacement therapy (Wimperis et al, 2011).
There is no data in CLL to indicate whether immunoglobulin replacement is helpful in patients with recurrent bacterial infections, a normal serum IgG level and a poor serum antibody response to conjugated pneumococcal vaccines, although a subset have IgG subclass deficiency (Freeman et al, 2012).
Dose and route of administration
Immunoglobulin may be administered intravenously 3–4 weekly using an initial dose of 0·4 g/kg, or by weekly subcutaneous infusion, aiming for a trough level of 6–8 g/l after 4 months of treatment (Wasserman et al, 2009). The immunoglobulin dose should be adjusted according to clinical response and trough levels repeated after three doses. Higher trough levels may be of benefit in patients with underlying co-morbidities, particularly bronchiectasis (Bayrakci et al, 2005; Lucas et al, 2010; Maarschalk-Ellerbroek et al, 2011).
Patients should be reviewed regularly, especially in the first 12 months of treatment. The incidence and severity of infections and the type and antibiotic sensitivity of bacteria causing breakthrough infections should be recorded.
Routine blood tests should include annual hepatitis B (HBsAg) and C (hepatitis C polymerase chain reaction) screening, annual save serum sample and 3–4 monthly trough IgG levels.
Treatment should be stopped if there is no improvement in the frequency or severity of bacterial infections after 1 year (Provan et al, 2008). If a decision to stop immunoglobulin replacement is made, this should take place over the summer months and be reviewed prior to the onset of winter. Patients should continue on prophylactic antibiotics and be provided with an additional antibiotic to be taken should breakthrough infection develop.
Recommendations: Grade B2
- Immunoglobulin replacement therapy should be considered as a means of reducing the incidence of bacterial infections in patients with a low serum IgG level who have experienced a previous major or recurrent minor bacterial infection despite optimal anti-bacterial prophylaxis.
- The goal should be to reduce the incidence of infection and the immunoglobulin dose should be adjusted accordingly.
- Patients should be reviewed regularly to evaluate the effectiveness of immunoglobulin replacement therapy and whether there is a continuing need for treatment.
- Patients who develop serious and/or recurrent infections despite antimicrobial prophylaxis and immunoglobulin replacement should be managed in conjunction with a microbiologist, infectious diseases specialist and/or immunologist.
There are no randomized studies showing that vaccination of any type alters infection rates or outcomes from acquired infections in CLL. Antibody response rates to pneumococcal and influenza vaccines are lower in patients with CLL than in healthy controls (Sinisalo et al, 2003, 2007; Pollyea et al, 2010). However, vaccination is safe and some patients respond particularly if vaccinated early in the disease and if conjugate vaccines, particularly to Streptococcus pneumoniae (Prevenar) and Haemophilus influenzae B (Hib) are used (Hartkamp et al, 2001; Sinisalo et al, 2011). Seasonal flu vaccination should also be given and for H1N1, two doses are advised (De Lavallade et al, 2011). The timing of vaccination in relation to treatments such as anti-CD20 antibody therapy, which deplete normal B cells, is also important. Failure to achieve protective antibody levels following seasonal and HINI influenza vaccination have been noted in patients with CLL and lymphomas vaccinated 2 weeks prior to, during or up to 6 months post-rituximab. (Pollyea et al, 2010; Yri et al, 2011).
Advice on the use of specific vaccines is available at http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_079917.
Recommendations Grade B2
- Vaccination against Streptococcus pneumoniae (using a conjugate vaccine) and Haemophilus influenzae type B is recommended at diagnosis. Patients who respond to vaccination and subsequently develop recurrent bacterial infections should be revaccinated if S. pneumoniae and Hib antibody levels have fallen.
- Annual vaccination against seasonal influenza and novel strains is recommended.
- Live vaccines such as polio, H. zoster and yellow fever should be avoided.
- Vaccinations should be avoided, if possible, 2 weeks prior to, during or up to 6 months after chemo-immunotherapy.
Suggested topics for audit
- Use of immunoglobulin replacement therapy.
- Vaccination policies.
- Screening for Hepatitis B/C pre chemo-immunotherapy.
- Screening for TP53 loss pre-treatment.
- Documentation of indication for treatment (according to IWCLL/National Cancer Institute guidance) in patient records.
- Patients should be screened for a TP53 abnormality pre-treatment (if they are candidates for agents that act through TP53-independent mechanisms)
- FCR is recommended for fit, previously untreated or relapsed patients who require treatment and who have not entered a clinical trial.
- Alemtuzumab (with pulsed high dose steroids) should be considered for previously untreated or relapsed patients with a TP53 abnormality and those with fludarabine-refractory disease who require treatment.
- Suitable patients with poor risk factors such as a TP53 abnormality and those who relapse early after intensive therapy should be considered for allogeneic transplantation.
- In view of the increasing number of new agents showing significant activity in phase 2 trials, and the extensive portfolio of trials now available in the UK, patients should be offered entry into clinical trials wherever possible.
While the advice and information in these guidelines is believed to be true and accurate at the time of going to press, neither the authors, the British Society for Haematology nor the publishers accept any legal responsibility for the content of these guidelines. The British Committee for Standards in Haematology (BCSH) will review this guideline on an annual basis to ensure it remains up-to-date guidance. Please see the website at www.bcshguidelines.com to see if the guideline has been updated or amendments added. The website will also show the date the guideline was last reviewed.
Acknowledgements and declarations of interest
None of the authors have declared a conflict of interest (or other statement as agreed between the writing group and the Task Force Chair. Task force membership at time of writing this guideline was Professor D Oscier, Dr C Dearden, Dr E Erem, Dr C Fegan, Dr G Follows, Professor P Hillmen, Dr T Illidge, Dr E Matutes, Dr D Milligan, Professor A Pettitt and Dr A Schuh. We would like to acknowledge Professor Barbara Bain and Anne Gardiner's support in preparing this document.